CN1138983A - 药物组合物的制备方法 - Google Patents
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Abstract
本发明涉及用于治疗或预防病毒感染的药物组合物的制备方法,其包括将式I化合物或其药用酸加成盐制成盖伦剂型。
Description
本发明涉及用于治疗或预防病毒感染的药物组合物的制备方法。
式I的化合物及其药用酸加成盐为新型的、并具备有价值的药理特性的化合物,具体说,其可以抑制病毒起源的蛋白酶,可用于预防或治疗病毒感染。尤其是由HIV及其它后病毒引起的感染。
本发明的内容包括:式I的化合物及前述的盐,以及用作有效的治疗物质,上述化合物及其盐的制备方法,用于该方法中的中间体,含有该化合物及其盐的药物,该化合物及盐在控制和预防疾病中的应用,尤其是用于治疗或预防病毒感染,以及应用该化合物及其盐制备用于治疗或预防病毒感染的药物。
式I化合物的药用酸加成盐包括:与无机酸所形成的盐,例如,无机酸包括:氢卤酸、如盐酸或氢溴酸、硫酸、硝酸。磷酸等,或与有机酸所形成的盐,有机酸包括例如:乙酸、枸椽酸、马来酸、富马酸、酒石酸、甲磺酸、对甲苯磺酸等。
根据本发明所述方法,前述的式I的化合物及其药用酸加成盐的制备是通过(a)2-〔(3-(s)-氨基-2(R)-羟基-4-苯丁基〕-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺(如下式)与具有下式的酸或其反应衍生物反应,或
(其中,R同前述定义)
(c)2-〔3(s)-〔(L-天冬酰胺酰)氨基〕-2(R)-羟基-4-苯丁基〕-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺(如下式)与生成苄氧基羰基或2-喹啉基羰基的试剂反应,及(d)如需要,将所得的式I的化合物转变成药用酸加成盐。
方法(a)中,式II的化合物与式III的酸的反应可按肽化学中已知方法进行,因此,当使用式III的酸时。反应优选在缩合剂,如羟基苯并三唑和二环已基碳化二亚胺存在下进行,该反应通常在惰性有机溶剂中如醚(如:乙醚,四氢呋喃等)或二甲基甲酰胺,且在低温下.适宜在约-10℃-+5℃间,尤其在约0℃时进行,适用的式III酸的反应衍生物为:例如:相应的酰基卤(如:酰基氯),酸酐,混合酸酐;活化酯等,当使用反应衍生物时,反应在有机碱(如:N-乙基吗啉,二异丙基乙胺等)存在下,在惰性有机溶剂如:卤代脂肪烃(如:二氯甲烷等)或醚(如:乙醚。四氢呋喃等)中,和在低温下进行,适宜的温度为-10℃~+5℃,特别是约在0℃时。
方法(b)中式IV化合物的还原可按已知的羰基还原为羟基的方法进行,因此,还原反应可使用络合金属氢化物,如碱金属硼氢化物特别是硼氢化钠,于适宜的有机溶剂,如醇(如:甲醇。乙醇、丙醇、异丙醇等)中进行。还原通常在室温下进行。按常规方法,可从所得混合物中分离出所需的2(R)-羟基异构体,如层析法等。
方法(c)中,用于生成苄氧基羰基的试剂为苄基氯甲酸酯,用于生成2-喹啉基羰基的试剂是其相应的酸或反应衍生物,如相应的酰基卤(如:酰基氯),酸酐。混合酸酐。活化酯等。式V的化合物与前述试剂的反应按与前述方法(a)相同的方法进行。
方法(d)中的式I的化合物转变成药用酸加成盐的反应可按常规方法进行,即用无机酸;如氢卤酸(如:盐酸或氢溴酸),硫酸,硝酸,磷酸等;或用有机酸:如:乙酸,柠檬酸。马来酸。富马酸。酒石酸、甲磺酸,对甲苯磺酸等处理该化合物。
用做方法(a)的起始物的式II的化合物为新的,其为本发明-项内容。
分子式II化合物的制备可按下列方法进行,如:将下式化合物(其中,R1代表氨基保护基(如:叔丁氧基羰基,或苄氧基羰基)。而X代表氯或溴原子〕与下式的N-叔丁基-十氢-(4as,8as)异喹啉-3(s)-羧酰胺反应。将所得的下式化合物还原,
(其中, R′同前述定义)从所得混合物中分离出所需的2(R)-羟基异构体,且从所得的下式化合物中去掉R′基,得到式II的化合物。
(其中,R1同前述定义)
当R1代表苄氧基羰基时的式VI化合物与式VII化合物的反应可按已知方法进行。如:在惰性有机溶剂中,如卤代脂肪烃(如:二氯甲烷),在碱存在下(如三烷基胺如三乙基胺等),且方便地在室温下进行。
式VIII的化合物还原为式IX化合物,随后将所需的2(R)-羟基异构体分离,该反应可按前述之本发明方法(b)进行(如:式IV化合物还原,并从所得混合物中分离出所需的2(R)-羟基异构体)。
从式IX化合物断裂去R1基的反应也可按已知方法进行,例如:使用强无机酸如氢卤酸或强有机酸(如:三氟醋酸等),方便地于0℃到室温下进行。可氢化断裂的氨基保护基R′还可以用氢在贵金属催化剂(如钯催化剂如钯一碳)存在下,在该反应条件下呈惰性的有机溶剂或溶剂混合物中进行(如:烷醇如乙醇,异丙醇等)烷基羧酸酯如乙酸乙酯等),可方便地在约室温下进行。
式II化合物的另一个制备方法为:首先将下式化合物与前述的式VII化合物反应,
(其中R1同前述定义)
该反应便于在惰性有机溶剂如醇(如甲醇等),二甲基甲酰胺等中进行,在较高温度下,约60℃~120℃进行,随后,如前述方法,去掉反应产物(前述之式IX化合物)中的R′基。
方法(b)中用做起始物的分子式IV的化合物可按下法制备,如:从式VIII化合物中去掉氨基保护基R′,将所得产物与式III的酸或其反应衍生物反应,该反应可按与方法(a)类似的方法进行。
方法(c)中用做起始物的式V的化合物为新的,其为本发明的另一项内容。
式V的化合物可通过从式I的化合物中去掉苄氧基羰基R(其中R代表苄氧基羰基或叔丁氧基羰基),得到与式I相对应的化合物,但其中R代表叔丁氧基羰基。该R为叔丁氧基羰基的化合物可通过式II的化合物与N-(叔丁氧基羰基)-L-天冬酰胺按方法(a)的方法反应制备。上述断裂反应与前述的从式VIII的化合物中断裂R′基的方法类似。
式III的起始物及其反应衍生物以及式VI,VII,和X的化合物到目前为止尚不属已知化合物或其类似物,其可按与已知化合物类似的方法或按实施例中将要叙述的方法或与其类似方法制备。而方法(c)中所用的试剂通常为已知化合物。
如前所述,式I的化合物及其药用酸加成盐抑制病毒起源的蛋白酶,可用于治疗或预防病毒感染,尤其是由HIV及其它后病毒引起的感染。
本发明化合物对HIV蛋白酶的体外抑制由下列试验得到验证。
HIV蛋白酶是从大肠杆菌中得到,该细菌的可溶性提取物经硫酸铵分馏(0~30%)得到部分纯化。蛋白酶活性用保护的六肽,琥珀酰-丝-亮-天冬酰胺-酪-脯-异亮异丁酰胺(S1)或保护的七肽:琥珀酰-缬-丝-谷氨酰胺-天冬酰胺-苯丙-脯-异亮异丁酰胺(S2)为底物测定。底物的断裂可通过分光光度检测N端脯氨酸,计算H-脯-异亮-异丁酰胺的产量来定量。
将1.25mM底物溶于含有0.125mg/ml吐温20的125mM柠檬酸盐缓冲液中(PH5。5)。往80ul该缓冲底物中加10ul不同浓度的试验化合物溶液(溶于甲醇或二甲基亚砜,用含0.1%吐温20的水稀释)和10μl蛋白酶。于37℃进行一段时间消化后,加1ml显色剂(含30μg/ml靛红和1.5mg/ml 2-(4-氯苯甲酰基)苯甲酸的含10%丙酮的乙醇(体积比)进行测定。溶液于水溶中加热,着色的残余物重新溶于1ml含1%焦棓酚。33%水的丙酮(重量/体积/体积)中,用分光光度法在599nm测定溶液的光密度。将试验化合物存在时H-脯-异亮异丁酰胺的生成量与对照品进行比较。利用所用的不同浓度试验化合物的曲线:测定50%抑制(I50)所需的试验化合物浓度。
式I化合物的体外抗病毒活性于下列检测中得到证实。
抗HIV活性:
该检测使用生长于C8166细胞(一种人CD4+T淋巴细胞系)中的HILV-III(RF株),使用RPMI 1640培养基,含有碳酸氢盐缓冲液。抗生素及10%胎牛血清。
细胞混悬液用10倍于TCD50的病毒感染,于37℃进行吸附90分钟,细胞用培养基洗3次,试验在6ml的组织培养管中进行,每管盛有含2×105感染细胞的1.5ml培养基,根据试验化合物的溶解性,将其溶于水溶性培养基或二甲基亚砜中,并加15ul该溶液于培养管中,培养物于37℃、和空气中含有5%二氧化碳的湿润的环境中孕育72小时,随后将培养物离心,将可分量的上清液用Nonidet P40溶解,并经抗原捕获检测,使用具有抗病毒蛋白24特殊活性的初级抗血清和辣根过氧化物酶检测系统,分光光度法测定所产生的颜色,且对试验物质的浓度画图,测定导致50%保护的浓度(I50)。
为确定抗病毒的选择性,基于染料吸收、代谢或放射标记的氨基酸结合的细胞毒性检测可与上述检测同时进行。
利用式I化合物进行上述试验所得结果列于下列表中
表
化合物IR | I50 | ||
HIV蛋白酶的抑制(uM) | 抗HIV活性(nM) | ||
S1 | S2 | ||
苄氧基羰基2-喹啉基羰基 | ≤0.024≤0.033 | ≤0.0027≤0.00037 | 202 |
式I的化合物及其药用酸加成盐可以药用,(如:以药物制剂的形式)。该药物制剂可以肠道给药:如口服(如:片剂。包衣片剂、糖衣丸剂、硬及软明胶胶囊剂。溶液剂。乳剂或混悬剂),经鼻给药(如鼻喷雾剂)或直肠给药(如:栓剂)。但是也可经非肠道给药,如肌注或静注(如:注射液剂型)。
为了制备片剂、包衣片。糖衣丸及软硬明胶囊,式I的化合物及其药用酸加成盐可用药用惰性的,无机或有机赋形剂处理,可使用乳糖,玉米淀粉或其衍生物,滑石,硬脂酸或其盐等做为片剂、糖衣丸、硬明胶胶囊的赋形剂。
软明胶胶囊适宜的赋形剂为:如植物油,蜡、脂肪。半固体和液体多元醇等。
制备溶液剂和糖浆剂适宜的赋形剂有:如水、多元醇、蔗糖。转化糖、葡萄糖等。
制备注射剂适宜的赋形剂有:如水、乙醇、多元醇、甘油、植物油等。
栓剂的适宜赋形剂有:例如:天然的或硬化油、蜡、脂肪、半固体或液体多元醇等。
药用制剂还可含有保鲜剂、助溶剂。增粘物质。稳定剂。润湿剂、乳化剂、甜味剂、着色剂、矫味剂、改变渗透压的盐、缓冲剂、包衣剂或抗氧化剂,还可含有其它有治疗价值的物质。
本发明中,式I的化合物及其药用酸加成盐可用于病毒感染的治疗和预防,尤其是逆病毒感染,剂量可在很宽的范围内变化,并可根据具体病例的需要而调整。通常,口服给药每日剂量为约3mg~3g,优选10mg~1g。(如:约每人300mg),优选分为1-3份剂量(可以等分)。当特别指明时,上述的剂量上限可被超出。
下列实施例说明了本发明。
实施例1
将含有56Img 2-〔3(S)-氨基-2(R)-羟基-4-苯基丁基〕-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺和272mg N-(苄氧基羰基)-L-天冬酰胺的20ml干燥四氢呋喃溶液于冰盐混合物中冷却,往其中加189mg羟基苯并三唑、161mg N-乙基吗啉和317mg二环己基碳化二亚胺,将混合物搅拌16小时,随后用乙酸乙酯稀释并过滤,滤液用碳酸氢钠水溶液和氯化钠溶液洗,蒸除溶剂,残余物经硅胶层析,用二氯甲烷/甲醇(9∶1)为流动相,从甲醇/乙醚中得到424mg 2-〔3(S)-〔〔N-(苄氧基羰基)-L一天冬酰胺酰基〕氨基〕-2(R)-羟基-4-苯基丁基〕-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺白色固体;MS;m/e 650〔M+H〕+:HMR:δ(d4CH3OH,400MHz):7.33(5H,m,PhCH2O),7.25(2H,m),7.18(2H,m),7.09(1H,m),5.05(2H,s,PhCH2O),4.42(1H,dd,AsnαJ=7.8,6.1),4.22(1H,m,-CH2CHCH(OH)-J=10.7,about 4,about 4),3.85(1H,m,-CHCH(OH)CH2-J=8.0,6.2,about 4),3.02(1H,dd,PhCH(H)CHJ=-13.9,about 4),3.02(1H,dd,1eq J=-12.0,small),2.69(1H,dd,PhCH(H)CH-J=-13.9,10.7),2.63(1H,dd,-CH(OH)CH(H)N-J=-12.6,8.0),2.62(1H,dd,H3ax J=about 11,small),2.57(1H,dd,Asnβ1 J=-15.2,6.1),2.38(1H,dd,Asn β2 J=-15.2,7.8),2.19(1H,dd,-CH(OH)CH(H)N-J=-12.6,6.2),2.17(1H,dd,1axJ=-12.0,3.2),2.07(1H,m,H4ax J=-12.7,about 11,about 11.5),1.78(1H,m,H4a J4a-4ax=about 11.5,J4a-4eq=small,J4a-8a=small)163(1H,m,H8aJ8a-1ax=3.2,J8a-1eq=small,J8a-4a=small1.35(1H,m,H4eqJ=-12.7,small,small),1.30(9H,s,t-butyl),2.0-1.2(8H,m).用做起始物的2-〔3(S)-氨基- 2(R)-羟基-4-苯基丁基〕-N-叔丁基-十氢-(4as,8as)-异喹啉-3(S)-羧酰胺如下述方法制备。(i)将含有12.676g(71.6mmol)的1,2,3,4-四氢-3(S)-异喹啉羧酸(Chem·Pharm。Bull,1983,31,312)的200ml 90%乙酸混悬液于80℃,于140大气压下,在5%铑-碳上氢化24小时,混合物冷至室温,将催化剂滤除,蒸发滤液,得到的胶状物溶于10ml乙酸乙酯,将其缓慢加到100ml猛烈搅拌的异丙醚中,生成树脂状沉淀。上清液用倾析法除去沉淀用热乙酸乙酯提取,将该热溶液倒入猛烈搅拌的150ml乙醚/异丙醚(1∶1)的混合物中,得到浅灰色固体,过滤收集,用乙醚洗并干燥,得到5.209g+氢异喹啉-3(s)-羧酸的混合物,其中包括:主要为(约65%)为4as,8as异构体,和4aR,8aR异构体(约25%)及大约10%的反向异构体;MS:m/e 184〔M+H〕+。(ii)将9.036g(49.4mmol)的前述+氢异喹啉-3(S)-羧酸的混合物溶于50ml(50mmol)的1M氢氧化钠溶液中,所得溶液冷至0℃,在冷却保持0~5℃温度下,在1小时内往其中滴加7.40ml(51.87mmol)苄基氯甲酸酯和58.7ml(58.7mmol)1M氢氧化钠溶液,随后将混合物再搅拌2小时,此时混合物升至室温。往其中加100ml乙醚,混合物被过滤,除去不溶的R,R-异构体,滤液的水层被分离出,加浓盐酸调pH1.5~2,得到油状沉淀物,混合物用乙酸乙酯提取两次,每次用100mml,合并的有机相用水洗,无水硫酸钠干燥,蒸发得到油状物,该油状物溶于35ml乙酸乙酯,将2.85ml(25mmol)环己胺加入,过滤收集白色沉淀,通过甲醇/乙酸乙酯几次分级重结晶,得到2.38g 2-(苄氧基羰基)-十氢-(4as,8as)-异喹啉-3(S)-羧酸的环己胺盐:MS:m/e 318〔M+H〕+。(iii)将2.334g的2-(苄氧基羰基)-十氢-(4as,8as)-异喹啉-3(s)-羧酸的环己胺盐分配于50ml乙酸乙酯和50ml 10%柠檬溶液中,分出有机相,用水洗,过滤,蒸发得到1.87g 2-(苄氧基羰基)-十氢-(4as,8as)-异喹啉-3(S)-羧酸为无色胶状物:MS:m/e 318(M+H)+。(IV)将含有0.634g(2.0mmol)2-(苄氧基羰基)-十氢-(4as,8as)-异喹啉-3(s)-羧酸的6ml二甲氧基乙烷溶液用0.23g(2.0mmol)的N-羟基琥珀酰亚胺和0.412g(2.0mmol)二环己基碳化二亚胺处理,混合物于室温下搅拌18小时,混合物过滤,蒸发滤液得到0.879g浅黄色油状物,即前述酸的N-羟基琥珀酰亚胺酯,将含有0.828g(2.0mmol)前述的N-羟基琥珀酰亚胺酯的5ml二氯甲烷溶液搅拌,冷至0℃,用0.219g(3.0mmol)叔丁胺处理,混合物于0℃搅拌2小时,随后于室温搅拌4.5小时,混合物随后用2M盐酸,碳酸钠溶液,和氯化钠溶液洗涤,无水硫酸镁干燥,蒸发,残余物溶于20ml乙醚,并过液,蒸发滤液,得到0.712g 2-(苄氧基羰基)-No-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺白色固体:MS:m/e373〔M+H〕+。(V)将含有0.689g(1.85mmol)2-(苄氧基羰基)-N-叔丁基-十氢-(4ao,8as)-异喹啉-3(s)-羧酰胺的20ml乙醇溶液在室温,大气压下,且有0.01g 10%钯一碳存在下氢化反应18小时,过滤除去催化剂,蒸发除去溶剂,得到一定产率的N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺,为澄清油状物;MS:m/e 239〔M+H〕+,其未经进一步纯化而用于下一步反应。(VI)将含有440mg N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺和549mg 3(s)-(苄氧基甲酰胺基)-1,2(s)-环氧-4-苯基丁烷的6ml乙醇溶液于60℃搅拌7小时,再加54mg 3(s)-(苄氧基甲酰胺基)-1,2(s)-环氧-4-苯基丁烷,将该溶液于20℃搅拌16小时。蒸发除去溶剂,残余物经硅胶层析(用乙醚/正己烷/甲醇(47.5∶47.55)做流动相,得到771mg 2-〔3(s)-(苄氧基甲酰胺基)-2(R)-羟基-4-苯基丁基-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺白色固体,MS:m/e 536(M+H〕+。(VII)含有747mg 2-〔3(s)-(苄氧基甲酰胺基)-2(R)-羟基-4-苯基丁基-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺的40ml乙醇溶液于10%的钯一碳上,于20℃,大气压下氢化反应5小时,过滤除去催化剂,蒸发滤液得到561mg 2-〔3(s)-氨基-2(R)-羟基-4-苯基丁基〕-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺,米色固体,不经进一步纯化而用于下一步骤。
实施例2
含有154mg 2-〔3(s)-〔(L-天冬酰胺酰基)氨基〕-2(R)-羟基-4-苯基丁基〕-N-叔丁基一十氢一(4as,8as)-异喹啉-3(s)-羧酰胺和52mg喹哪啶酸的6ml干燥四氢呋喃溶液于冰盐混合物中冷却。随后加41mg羟基苯并三唑,35mg N-乙基吗啉和68mg二环己基碳化二亚胺,混合物搅拌64小时,随后用乙酸乙酯稀释,并过滤,滤液用碳酸氢钠水溶液,和氯化钠水溶液洗,蒸发,残余物经硅胶层析,用二氯甲烷/甲醇(9∶1)做流动相,得到50mg M-叔丁基-十氢-2-〔2(R)-羟基-4--苯基-3(s)-〔〔N-(2-喹啉基羰基)-L-天冬酰胺酰基〕氨基〕-丁基〕-(4as,8as)-异喹啉-3(s)-羧酰胺白色固体;MS:m/e671〔M+H〕+:NMR:δ(d4 CH3OH400MHz):8.52(1H,m),8.18(1H,m),8.14(1H,m),8.02(1H,m),7.84(1H,m),7.69(1H,m),7.18(2H,m),6.90(2H,m),6.72(1H,m),4.93(1H,dd,AsnαCH J=6.6,6.8),4.27(1H,m,-CH2CHCH(OH)-J=3.8,3.8,11.0),3.89(1H,m,-CHCH(OH)CH2-J=7.2,6.4,3.8),3.06(1H,dd,H1eqJ=-12.0,3.0),3.02(1H,dd,PhCH(H)CH-J=-14.0,3.8),2.77(1H,dd,Asnβ1 J=-15.6,6.6),2.68(1H,dd,Asnβ2J=-15.6,6.8),2.68(1H,dd,PhCH(H)CH-J=-14.0,11.0),about 2.68(1H,dd,-CH(OH)CH(H)N-J=-12.0,7.2)2.63(1H,dd,H3 J=110,22)2.22(1H dd-CH(OH)CH(H)N-J=-12.0,6.4),2.18(1H,dd,H1axJ=-12.0,2.2),2.06(1H,m,H4ax J=-11.0,11.0,11.0)1.78(1H,m,4a J4a-4ax=11.04a-4eq=about4,J4a-8a=about 4),1.65(1H,m,8a J8a-1ax=2.2J8a-1eq=3.0 J8a-4a=about 4),1.37(1H,m,H4eqJ=-11.0,2.2,about 4),1.30(9H,6,t-butyl),2.0-1.2(8H,m).
用做起始物的2-〔3(s)-〔(L-天冬酰胺酰基)氨基〕-2(R)-羟基-4-苯基丁基〕-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺按下列方法制备:
将含有195mg 2-〔3(s)-〔〔N-(苄氧基羰基)-L-天冬酰胺酰基〕氨基〕-2(R)-羟基-4-苯基丁基〕-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺的20ml乙醇溶液于室温下,大气压下,在10mg 10%的钯一碳上氢化反应18小时,过滤除去催化剂,减压蒸发滤液。得到154mg 2-〔3(s)-〔(L-夫冬酰胺酰基)氨基〕-2-(R)-羟基-4-苯基丁基〕-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺,其不经纯化而用于下步反应。
实施例3
将含有287mg N-(2-喹啉基羰基)-L-天冬酰胺和401mg 2〔3(s)-氨基-2(R)-羟基-4-苯基丁基〕-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺(于实施例1(i)-(VII)制备)的3ml四氢呋喃溶液冷至-10℃,往其中加163mg 3-羟基-1,2,3-苯并三嗪-4(3H)-酮和220mg二环己基碳化二亚胺,混合物于-10℃搅拌2小时,于20℃搅拌16小时,随后用乙酸乙酯稀释并过滤,滤液用饱和碳酸氢钠溶液和饱和氯化钠溶液洗,并蒸发,残余物经硅胶层析;用含4%(体积)甲醇的二氯甲烷作流动相,得到537mg N-叔丁基-十氢-2-〔2(R)-羟基-4-苯基-3(s)-〔〔N-(2-喹啉基羰基)-L-天冬酰胺酰基〕氨基〕丁基〕-(4as,8as)-异喹啉-3(s)-羧酰胺,其与实例2第一段中所得到的产物相同。
用做起始物的N-(2-喹啉基羰基)-L-天冬酰胺按下列方法制备:
将含有540mg喹哪啶酸琥珀酰胺酯和300mg L-天冬酰胺单水合物及2ml二甲基甲酰胺的混合物于20℃搅拌96小时,蒸除溶剂,得到的白色固体残余物于10ml二氯甲烷中猛烈搅拌,过滤用二氯甲烷洗,得到431mg N-(2 -喹啉基羰基)-L一天冬酰胺,白色固体;MS:m/e 288〔M+H〕+。
下列实施例介绍了以式I的化合物或其药用酸加成盐为活性成分的药物制剂的制备方法:
实施例A
活性成分的水溶液经无菌过滤。温热时与无菌明胶溶液混合,其含有酚做防腐剂。每1,00ml所得溶液含有3.0mg活性成分,150.0mg明胶4.7mg酚及蒸馏水加至1.0ml,混合物在无菌操作条件下充入容量为1.0ml的管形瓶中。
Claims (1)
1.用于治疗或预防病毒感染的药物组合物的制备方法,其包括将式I化合物或其药用酸加成盐制成盖伦剂型,其中R为苄氧基羰基或2-喹啉基羰基。
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